To investigate the role of p53 in response to genotoxic damage and oncogenesis we have constructed a unique knock-in mouse in which the endogenous p53 gene has been replace with one encoding a p53ER TAMfusion protein. In such animals, and in cells derived from them, competence for wild type p53 function appears to be completely dependent upon supply of the synthetic activating ligand 4-hydroxytamoxifen. We will validate and optimize this model and use it to establish the role, dependence and timing of p53 status in the response to DNA damage and oncogene activation in cells in vitro. We will also determine the efficacy of sustained or episodic p53 functional restoration in vivo in the response to DNA damage and in the prevention and regression of lymphoid and skin tumors. MDM2 and MDMX proteins are critical regulators of p53 whose loss leads to early embryonic lethality unless p53 is also absent. We will use our switchable p53ER TAMKI mice to establish the mechanism and timing of the dependency of MDM2/MDMX on p53 status and to explore p53 independent functions of both proteins. Our model will provide unique insights into the mechanism, timing and duration of p53-mediated tumor suppression as well unique information on the relationship between p53 and its MDM2 and MDMX regulators.